Of the 2,759 participants who provided data on hot flushes at baseline, 16% (n = 434) reported clinically significant hot flushes, defined as hot flushes that were bothersome “some” to “all” of the time. The remaining 84% of women (n = 2,325) were bothered by hot flushes “a little” or “none of the time.” The proportion of women with clinically significant hot flushes at baseline did not differ significantly between the EPT and placebo groups (15% vs 17%; P = 0.16).
Participants with clinically significant hot flushes at baseline tended to be younger, nonwhite, less educated, and more recently postmenopausal, as well as to have higher diastolic blood pressure, higher LDL cholesterol levels, higher triglyceride levels, higher body mass index, worse self-reported overall health, higher rates of prior estrogen use, and greater prevalence of prior MI (). In multivariable analysis, clinically significant flushing was independently associated with younger age, nonwhite race, fewer years of education, fewer years since menopause, higher diastolic blood pressure, body mass index greater than 27 kg/m2, poor or fair self-reported health, prior estrogen use, and prior MI (). Adherence to the study medication during the course of the trial did not differ substantially among women with and without clinically significant flushing at baseline (71% of women without flushing and 70% of women with flushing demonstrated ≥80% adherence to study medications for 4 years based on pill counts; P = 0.66).
Baseline characteristics of participants by hot flush status
Cardiovascular risk factors associated with hot flushes at baseline
Among participants reporting clinically significant hot flushes at baseline, women randomized to placebo had somewhat higher average triglyceride levels at baseline compared with those randomized to EPT (mean [±SD] triglyceride levels = 185 [±64] mg/dL vs 160 [±61] mg/dL; P = 0.01), but did not differ with regard to other CHD risk factors (P > 0.05 for age, race, education, smoking, diabetes, blood pressure, LDL cholesterol, high-density lipoprotein cholesterol, years since menopause, body mass index, exercise, alcohol use, overall health, prior estrogen use, history of congestive heart failure, prior percutaneous coronary revascularization, prior coronary artery bypass graft surgery, and prior MI). Among participants without flushing at baseline, no significant differences in baseline CHD risk factors were observed among those randomized to placebo versus EPT (P > 0.05 for all).
Among the 2,325 women reporting no significant hot flushes at baseline, 84 CHD events were observed during the first year of treatment, and a total of 305 events were observed during the entire trial period (). Forty-seven of the first-year events occurred in those randomized to EPT and 37 in those randomized to placebo (hazard ratio [HR] for the effects of EPT in the first year = 1.32; 95% CI, 0.86-2.03; P = 0.21; ). Among the 434 women reporting clinically significant hot flushes at baseline, 11 CHD events occurred in the first year of treatment and a total of 56 events during the entire trial period. Of the 11 first-year events, 10 events occurred among women in the EPT group versus ony 1 in the placebo group (HR for the effects of EPT = 9.01; 95% CI, 1.15-70.35; P = 0.04) (P = 0.07 for interaction between hot flushes and treatment). There was no evidence of an interaction of hot flushes and treatment assignment after the first year of treatment (P > 0.10 for all).
Coronary heart disease events by treatment assignment, baseline hot flush status, and year of study
The effect of estrogen + progestin treatment on risk of coronary heart disease events, by baseline hot flush status
The interaction between hot flushes and hormone therapy in the first year of treatment was not diminished and, in some cases, became even more significant after adjustment for potential competing interactions with other CHD risk factors found to be associated with flushing at baseline, including age, race, years of education, years since menopause, diastolic blood pressure, body mass index, self-reported health, prior estrogen use, and prior MI (P = 0.03 for interaction to 0.08 for all).